Cancer Cell-Specific Major Histocompatibility Complex II Expression as a Determinant of the Immune Infiltrate Organization and Function in the NSCLC Tumor Microenvironment

IntroductionIn patients with NSCLC, the prognostic significance of the tumor microenvironment (TME) immune composition has been revealed using single- or dual-marker staining on sequential tissue sections. Although these studies reveal that relative abundance and localization of immune cells are important parameters, deeper analyses of the NSCLC TME are necessary to refine the potential application of these findings to clinical care. Currently, the complex spatial relationships between cells of the NSCLC TME and potential drivers contributing to its immunologic composition remain unknown.MethodsWe used multispectral quantitative imaging on the lung adenocarcinoma TME in 153 patients with resected tumors. On a single slide per patient, we evaluated the TME with markers for CD3, CD8, CD14, CD19, major histocompatibility complex II (MHCII), cytokeratin, and 4′,6-diamidino-2-phenylindole (DAPI). Image analysis, including tissue segmentation, phenotyping, and spatial localization, was performed.ResultsSpecimens wherein greater than or equal to 5% of lung cancer cells expressed MHCII (MHCII^hi TME) had increased levels of CD4⁺ and CD8⁺ T cells and CD14⁺ cell infiltration. In the MHCII^hi TME, the immune infiltrate was closer to cancer cells and expressed an activated phenotype. Morphologic image analysis revealed cancer cells in the MHCII^hi TME more frequently interfaced with CD4⁺ and CD8⁺ T cells. Patients with an MHCII^hi TME experienced improved overall survival (p = 0.046).ConclusionsLung cancer cell-specific expression of MHCII associates with levels of immune cell infiltration, spatial localization, and activation status within the TME. This suggests that cancer cell-specific expression of MHCII may represent a biomarker for the immune system’s recognition and activation against the tumor.     

ONRAB® oral rabies vaccine is shed from,but does not persist in,captive mammals

ONRAB® is a human adenovirus rabies glycoprotein recombinant vaccine developed to control rabies in wildlife. To support licensing and widespread use of the vaccine, safety studies are needed to assess its potential residual impact on wildlife populations. We examined the persistence of the ONRAB® vaccine virus in captive rabies vector and non-target mammals. This research complements work on important rabies vector species (raccoon, striped skunk, and red fox) but also adds to previous findings with the addition of some non-target species (Virginia opossum, Norway rats, and cotton rats) and a prolonged period of post vaccination monitoring (41 days). Animals were directly inoculated orally with the vaccine and vaccine shedding was monitored using quantitative real-time PCR applied to oral and rectal swabs. ONRAB® DNA was detected in both oral and rectal swabs from 6 h to 3 days post-inoculation in most animals, followed by a resurgence of shedding between days 17 and 34 in some species. Overall, the duration over which ONRAB® DNA was detectable was shorter for non-target mammals, and by day 41, no animal had detectable DNA in either oral or rectal swabs. All target species, as well as cotton rats and laboratory-bred Norway rats, developed robust humoral immune responses as measured by competitive ELISA, with all individuals being seropositive at day 31. Similarly, opossums showed good response (89% seropositive; 8/9), whereas only one of nine wild caught Norway rats was seropositive at day 31. These results support findings of other safety studies suggesting that ONRAB® does not persist in vector and non-target mammals exposed to the vaccine. As such, we interpret these data to reflect a low risk of adverse effects to wild populations following distribution of ONRAB® to control sylvatic rabies.     

IFI 30、PD-L1在人脑胶质瘤中的表达及与病人预后的关系

目的 探讨γ干扰素诱导蛋白30（IFI 30）、程序性死亡因子配体1（PD-L1）在人脑胶质瘤中的表达及与病人预后的关系。方法 选择2015年5月~2019年5月手术切除的103例人脑胶质瘤组织和瘤旁组织，采用免疫组织化学染色检测IFI 30、PD-L1表达情况。随访24个月，记录无进展生存期和总生存期。结果 胶质瘤组织IFI 30、PD-L1高表达率[分别为70.87%（73/103）、68.93%（71/103）]明显高于瘤旁组织[分别为19.42%（20/103）、21.36%（22/103）；P<0.001]。胶质瘤组织IFI 30表达水平与PD-L1表达水平呈明显正相关（r=0.583，P<0.05）。随访24个月，生存75例，死亡28例；多因素logistic回归分析显示，IFI 30高表达、PD-L1高表达是增加病人死亡风险的独立危险因素（P<0.05）。生存曲线分析显示，IFI 30高表达组2年累积生存率（64.52%）和2年累积无进展生存率（65.56%）均明显低于低表达组（分别为82.25%、89.45%；P<0.05）。PD-L1高表达组2年累积生存率（61.78%）和2年累积无进展生存率（60.14%）均明显低于低表达组（分别为88.52%、79.86%；P<0.05）。结论 人脑胶质瘤组织IFI 30、PD-L1呈高表达，与病人不良预后密切相关。     

Age-related variations in gene expression patterns of renal cell carcinoma

Background

Clear cell renal cell carcinoma (ccRCC) is known to occur across the adult lifetime traversing the spectrum of age-related organismal changes. Little is known as to how the aging process may affect the course of renal cell carcinoma (RCC) and the repertoire of genes involved.

Effect of lacosamide on ethanol induced conditioned place preference and withdrawal associated behavior in mice: Possible contribution of hippocampal CRMP-2

BackgroundExcessive consumption of ethanol is known to activate the mTORC1 pathway and to enhance the Collapsin Response Mediator Protein-2 (CRMP-2) levels in the limbic region of brain. The latter helps in forming microtubule assembly that is linked to drug taking or addiction-like behavior in rodents. Therefore, in this study, we investigated the effect of lacosamide, an antiepileptic drug and a known CRMP-2 inhibitor, which binds to CRMP-2 and inhibits the formation of microtubule assembly, on ethanol-induced conditioned place preference (CPP) in mice.MethodsThe behavior of mice following ethanol addiction and withdrawal was assessed by performing different behavioral paradigms. Mice underwent ethanol-induced CPP training with alternate dose of ethanol (2 g/kg, po) and saline (10 ml/kg, po). The effect of lacosamide on the expression of ethanol-induced CPP and on ethanol withdrawal associated anxiety and depression-like behavior was evaluated. The effect of drug on locomotor activity was also assessed and hippocampal CRMP-2 levels were measured.ResultsEthanol-induced CPP was associated with enhanced CRMP-2 levels in the hippocampus. Lacosamide significantly reduced the expression of ethanol-induced CPP and alleviated the levels of hippocampal CRMP-2 but aggravated withdrawal-associated anxiety and depression in mice.ConclusionThe present study demonstrated the beneficial effect of lacosamide in attenuation of expression of ethanol induced conditioned place preference via reduction of hippocampal CRMP-2 level. These findings suggest that lacosamide may be investigated further for ethanol addiction but not for managing withdrawal.     

Multidimensional Ultrasound Doppler Signal Analysis for Fetal Activity Monitoring

Fetal activity parameters such as movements, heart rate and the related parameters are essential indicators of fetal wellbeing, and no device provides simultaneous access to and sufficient estimation of all of these parameters to evaluate fetal health. This work was aimed at collecting these parameters to automatically separate healthy from compromised fetuses. To achieve this goal, we first developed a multi-sensor–multi-gate Doppler system. Then we recorded multidimensional Doppler signals and estimated the fetal activity parameters via dedicated signal processing techniques. Finally, we combined these parameters into four sets of parameters (or four hyper-parameters) to determine the set of parameters that is able to separate healthy from other fetuses. To validate our system, a data set consisting of two groups of fetal signals (normal and compromised) was established and provided by physicians. From the estimated parameters, an instantaneous Manning-like score, referred to as the ultrasonic score, was calculated and was used together with movements, heart rate and the associated parameters in a classification process employing the support vector machine method. We investigated the influence of the sets of parameters and evaluated the performance of the support vector machine using the computation of sensibility, specificity, percentage of support vectors and total classification error. The sensitivity of the four sets ranged from 79% to 100%. Specificity was 100% for all sets. The total classification error ranged from 0% to 20%. The percentage of support vectors ranged from 33% to 49%. Overall, the best results were obtained with the set of parameters consisting of fetal movement, short-term variability, long-term variability, deceleration and ultrasound score. The sensitivity, specificity, percentage of support vectors and total classification error of this set were respectively 100%, 100%, 35% and 0%. This indicated our ability to separate the data into two sets (normal fetuses and pathologic fetuses), and the results highlight the excellent match with the clinical classification performed by the physicians. This work indicates the feasibility of detecting compromised fetuses and also represents an interesting method of close fetal monitoring during the entire pregnancy.